Berg J.M., Tymoczko J.L., Stryer L. Biochemistry
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Figure 1.14. Protein Folding. Protein folding entails the transition from a disordered mixture of unfolded molecules to a
relatively uniform solution of folded protein molecules.
I. The Molecular Design of Life 1. Prelude: Biochemistry and the Genomic Revolution 1.3. Chemical Bonds in Biochemistry
Figure 1.15. The Hydrophobic Effect. The aggregation of nonpolar groups in water leads to an increase in entropy
owing to the release of water molecules into bulk water.
I. The Molecular Design of Life 1. Prelude: Biochemistry and the Genomic Revolution
1.4. Biochemistry and Human Biology
Our understanding of biochemistry has had and will continue to have extensive effects on many aspects of human
endeavor. First, biochemistry is an intrinsically beautiful and fascinating body of knowledge. We now know the essence
and many of the details of the most fundamental processes in biochemistry, such as how a single molecule of DNA
replicates to generate two identical copies of itself and how the sequence of bases in a DNA molecule determines the
sequence of amino acids in an encoded protein. Our ability to describe these processes in detailed, mechanistic terms
places a firm chemical foundation under other biological sciences. Moreover, the realization that we can understand
essential life processes, such as the transmission of hereditary information, as chemical structures and their reactions has
significant philosophical implications. What does it mean, biochemically, to be human? What are the biochemical
differences between a human being, a chimpanzee, a mouse, and a fruit fly? Are we more similar than we are different?
Second, biochemistry is greatly influencing medicine and other fields. The molecular lesions causing sickle-cell anemia,
cystic fibrosis, hemophilia, and many other genetic diseases have been elucidated at the biochemical level. Some of the
molecular events that contribute to cancer development have been identified. An understanding of the underlying defects
opens the door to the discovery of effective therapies. Biochemistry makes possible the rational design of new drugs,
including specific inhibitors of enzymes required for the replication of viruses such as human immunodeficiency virus
(HIV). Genetically engineered bacteria or other organisms can be used as "factories" to produce valuable proteins such
as insulin and stimulators of blood-cell development. Biochemistry is also contributing richly to clinical diagnostics. For
example, elevated levels of telltale enzymes in the blood reveal whether a patient has recently had a myocardial
infarction (heart attack). DNA probes are coming into play in the precise diagnosis of inherited disorders, infectious
diseases, and cancers. Agriculture, too, is benefiting from advances in biochemistry with the development of more
effective, environmentally safer herbicides and pesticides and the creation of genetically engineered plants that are, for
example, more resistant to insects. All of these endeavors are being accelerated by the advances in genomic sequencing.
Third, advances in biochemistry are enabling researchers to tackle some of the most exciting questions in biology and
medicine. How does a fertilized egg give rise to cells as different as those in muscle, brain, and liver? How do the senses
work? What are the molecular bases for mental disorders such as Alzheimer disease and schizophrenia? How does the
immune system distinguish between self and nonself? What are the molecular mechanisms of short-term and long-term
memory? The answers to such questions, which once seemed remote, have been partly uncovered and are likely to be
more thoroughly revealed in the near future.
Because all living organisms on Earth are linked by a common origin, evolution provides a powerful organizing theme
for biochemistry. This book is organized to emphasize the unifying principles revealed by evolutionary considerations.
We begin in the next chapter with a brief tour along a plausible evolutionary path from the formation of some of the
chemicals that we now associate with living organisms through the evolution of the processes essential for the
development of complex, multicellular organisms. The remainder of Part I of the book more fully introduces the most
important classes of biochemicals as well as catalysis and regulation. Part II, Transducing and Storing Energy, describes
how energy from chemicals or from sunlight is converted into usable forms and how this conversion is regulated. As we
will see, a small set of molecules such as adenosine triphosphate (ATP) act as energy currencies that allow energy,
however captured, to be utilized in a variety of biochemical processes. This part of the text examines the important
pathways for the conversion of environmental energy into molecules such as ATP and uncovers many unifying
principles. Part III, Synthesizing the Molecules of Life, illustrates the use of the molecules discussed in Part II to
synthesize key molecular building blocks, such as the bases of DNA and amino acids, and then shows how these
precursors are assembled into DNA, RNA, and proteins. In Parts II and III, we will highlight the relation between the
reactions within each pathway and between those in different pathways so as to suggest how these individual reactions
may have combined early in evolutionary history to produce the necessary molecules. From the student's perspective, the
existence of features common to several pathways enables material mastered in one context to be readily applied to new
contexts. Part IV, Responding to Environmental Changes, explores some of the mechanisms that cells and multicellular
organisms have evolved to detect and respond to changes in the environment. The topics range from general
mechanisms, common to all organisms, for regulating the expression of genes to the sensory systems used by human
beings and other complex organisms. In many cases, we can now see how these elaborate systems evolved from
pathways that existed earlier in evolutionary history. Many of the sections in Part IV link biochemistry with other fields
such as cell biology, immunology, and neuroscience. We are now ready to begin our journey into biochemistry with
events that took place more than 3 billion years ago.
I. The Molecular Design of Life 1. Prelude: Biochemistry and the Genomic Revolution
Appendix: Depicting Molecular Structures
The authors of a biochemistry text face the problem of trying to present three-dimensional molecules in the two
dimensions available on the printed page. The interplay between the three-dimensional structures of biomolecules and
their biological functions will be discussed extensively throughout this book. Toward this end, we will frequently use
representations that, although of necessity are rendered in two dimensions, emphasize the three-dimensional structures of
molecules.
Stereochemical Renderings
Most of the chemical formulas in this text are drawn to depict the geometric arrangement of atoms, crucial to chemical
bonding and reactivity, as accurately as possible. For example, the carbon atom of methane is sp
3
hybridized and
tetrahedral, with H-C-H angles of 109.5 degrees while the carbon atom in formaldehyde is sp
2
hybridized with bond
angles of 120 degrees.
To illustrate the correct stereochemistry about carbon atoms, wedges will be used to depict the direction of a bond into or
out of the plane of the page. A solid wedge with the broad end away from the carbon denotes a bond coming toward the
viewer out of the plane. A dashed wedge, with the broad end of the bond at the carbon represents a bond going away
from the viewer into the plane of the page. The remaining two bonds are depicted as straight lines.
Fischer Projections
Although more representative of the actual structure of a compound, stereochemical structures are often difficult to draw
quickly. An alternative method of depicting structures with tetrahedral carbon centers relies on the use of Fischer
projections.
In a Fischer projection, the bonds to the central carbon are represented by horizontal and vertical lines from the
substituent atoms to the carbon atom, which is assumed to be at the center of the cross. By convention, the horizontal
bonds are assumed to project out of the page toward the viewer, whereas the vertical bonds are assumed to project into
the page away from the viewer. The Glossary of Compounds found at the back of the book is a structural glossary of the
key molecules in biochemistry, presented both as stereochemically accurate structures and as Fisher projections.
For depicting molecular architecture in more detail, five types of models will be used: space filling, ball and stick,
skeletal, ribbon, and surface representations (Figure 1.16). The first three types show structures at the atomic level.
1. Space-filling models. The space-filling models are the most realistic. The size and position of an atom in a space-
filling model are determined by its bonding properties and van der Waals radius, or contact distance (Section 1.3.1). A
van der Waals radius describes how closely two atoms can approach each other when they are not linked by a covalent
bond. The colors of the model are set by convention.
Space-filling models of several simple molecules are shown in Figure 1.17.
2. Ball-and-stick models. Ball-and-stick models are not as realistic as space-filling models, because the atoms are
depicted as spheres of radii smaller than their van der Waals radii. However, the bonding arrangement is easier to see
because the bonds are explicitly represented as sticks. In an illustration, the taper of a stick, representing parallax, tells
which of a pair of bonded atoms is closer to the reader. A ball-and-stick model reveals a complex structure more clearly
than a space-filling model does.
3. Skeletal models. An even simpler image is achieved with a skeletal model, which shows only the molecular
framework. In skeletal models, atoms are not shown explicitly. Rather, their positions are implied by the junctions and
ends of bonds. Skeletal models are frequently used to depict larger, more complex structures.
As biochemistry has advanced, more attention has been focused on the structures of biological macromolecules and their
complexes. These structures comprise thousands or even tens of thousands of atoms. Although these structures can be
depicted at the atomic level, it is difficult to discern the relevant structural features because of the large number of atoms.
Thus, more schematic representations
ribbon diagrams and surface representations have been developed for the
depiction of macromolecular structures in which atoms are not shown explicitly (Figure 1.18).
4. Ribbon diagrams. These diagrams are highly schematic and most commonly used to accent a few dramatic aspects of
protein structure, such as the α helix (a coiled ribbon), the β strand (a broad arrow), and loops (simple lines), so as to
provide simple and clear views of the folding patterns of proteins.
5. Surface representations. Often, the interactions between macromolecules take place exclusively at their surfaces.
Surface representations have been developed to better visualize macromolecular surfaces. These representations display
the overall shapes of macromolecules and can be shaded or colored to indicate particular features such as surface
topography or the distribution of electric charges.
Key Terms
deoxyribonucleic acid (DNA)
double helix
ribonucleic acid (RNA)
protein
amino acid
genetic code
Eukarya
Bacteria
Archaea
eukaryote
prokaryote
covalent bond
resonance structure
electrostatic interaction
hydrogen bond
van der Waals interaction
entropy
enthalpy
free energy
hydrophobic effect
sterochemistry
Fischer projection
space-filling model
ball-and stick-model
skeletal model
ribbon diagram
surface presentation
I. The Molecular Design of Life 1. Prelude: Biochemistry and the Genomic Revolution Appendix: Depicting Molecular Structures
Figure 1.16. Molecular Representations. Comparison of (A) space-filling, (B) ball-and-stick, and (C) skeletal models
of ATP.
I. The Molecular Design of Life 1. Prelude: Biochemistry and the Genomic Revolution Appendix: Depicting Molecular Structures
Figure 1.17. Space-Filling Models. Structural formulas and space-filling representations of selected molecules are
shown.
I. The Molecular Design of Life 1. Prelude: Biochemistry and the Genomic Revolution Appendix: Depicting Molecular Structures
Figure 1.18. Alternative Representations of Protein Structure.
A ribbon diagram (A) and a surface representation (B)
of a key protein from the immune system emphasize different aspects of structure.
I. The Molecular Design of Life
2. Biochemical Evolution
Earth is approximately 4.5 billion years old. Remarkably, there is convincing fossil evidence that organisms
morphologically (and very probably biochemically) resembling certain modern bacteria were in existence 3.5 billion
years ago. With the use of the results of directed studies and accidental discoveries, it is now possible to construct a
hypothetical yet plausible evolutionary path from the prebiotic world to the present. A number of uncertainties remain,
particularly with regard to the earliest events. Nonetheless, a consideration of the steps along this path and the
biochemical problems that had to be solved provides a useful perspective from which to regard the processes found in
modern organisms. These evolutionary connections make many aspects of biochemistry easier to understand.
We can think of the path leading to modern living species as consisting of stages, although it is important to keep in
mind that these stages were almost certainly not as distinct as presented here. The first stage was the initial generation of
some of the key molecules of life
nucleic acids, proteins, carbohydrates, and lipids by nonbiological processes. The
second stage was fundamental the transition from prebiotic chemistry to replicating systems. With the passage of time,
these systems became increasingly sophisticated, enabling the formation of living cells. In the third stage, mechanisms
evolved for interconverting energy from chemical sources and sunlight into forms that can be utilized to drive
biochemical reactions. Intertwined with these energy-conversion processes are pathways for synthesizing the
components of nucleic acids, proteins, and other key substances from simpler molecules. With the development of
energy-conversion processes and biosynthetic pathways, a wide variety of unicellular organisms evolved. The fourth
stage was the evolution of mechanisms that allowed cells to adjust their biochemistry to different, and often changing,
environments. Organisms with these capabilities could form colonies comprising groups of interacting cells, and some
eventually evolved into complex multicellular organisms.
This chapter introduces key challenges posed in the evolution of life, whose solutions are elaborated in later chapters.
Exploring a possible evolutionary origin for these fundamental processes makes their use, in contrast with that of
potential alternatives, more understandable.
I. The Molecular Design of Life 2. Biochemical Evolution
Natural selection, one of the key forces powering evolution, opens an array of improbable ecological niches to
species that can adapt biochemically. (Left) Salt pools, where the salt concentration can be greater than 1.5 M, would
seem to be highly inhospitable environments for life. Yet certain halophilic archaea, such as Haloferax mediterranei
(right), possess biochemical adaptations that enable them to thrive under these harsh conditions. [(Left) Kaj R. Svensson/
Science Photo Library/Photo Researchers; (right) Wanner/Eye of Science/Photo Researchers.]
I. The Molecular Design of Life 2. Biochemical Evolution
2.1. Key Organic Molecules Are Used by Living Systems
Approximately 1 billion years after Earth's formation, life appeared, as already mentioned. Before life could exist,
though, another major process needed to have taken place
the synthesis of the organic molecules required for living
systems from simpler molecules found in the environment. The components of nucleic acids and proteins are relatively
complex organic molecules, and one might expect that only sophisticated synthetic routes could produce them. However,
this requirement appears not to have been the case. How did the building blocks of life come to be?
2.1.1. Many Components of Biochemical Macromolecules Can Be Produced in Simple,
Prebiotic Reactions
Among several competing theories about the conditions of the prebiotic world, none is completely satisfactory or
problem-free. One theory holds that Earth's early atmosphere was highly reduced, rich in methane (CH
4
), ammonia
(NH
3
), water (H
2
O), and hydrogen (H
2
), and that this atmosphere was subjected to large amounts of solar radiation and
lightning. For the sake of argument, we will assume that these conditions were indeed those of prebiotic Earth. Can
complex organic molecules be synthesized under these conditions? In the 1950s, Stanley Miller and Harold Urey set out
to answer this question. An electric discharge, simulating lightning, was passed through a mixture of methane, ammonia,
water, and hydrogen (Figure 2.1). Remarkably, these experiments yielded a highly nonrandom mixture of organic
compounds, including amino acids and other substances fundamental to biochemistry. The procedure produces the
amino acids glycine and alanine in approximately 2% yield, depending on the amount of carbon supplied as methane.
More complex amino acids such as glutamic acid and leucine are produced in smaller amounts (Figure 2.2). Hydrogen
cyanide (HCN), another likely component of the early atmosphere, will condense on exposure to heat or light to produce
adenine, one of the four nucleic acid bases (Figure 2.3). Other simple molecules combine to form the remaining bases. A
wide array of sugars, including ribose, can be formed from formaldehyde under prebiotic conditions.
2.1.2. Uncertainties Obscure the Origins of Some Key Biomolecules
The preceding observations suggest that many of the building blocks found in biology are unusually easy to synthesize
and that significant amounts could have accumulated through the action of nonbiological processes. However, it is
important to keep in mind that there are many uncertainties. For instance, ribose is just one of many sugars formed under
prebiotic conditions. In addition, ribose is rather unstable under possible prebiotic conditions. Futhermore, ribose occurs
in two mirror-image forms, only one of which occurs in modern RNA. To circumvent those problems, the first nucleic
acid-like molecules have been suggested to have been bases attached to a different backbone and only later in
evolutionary time was ribose incorporated to form nucleic acids as we know them today. Despite these uncertainties, an
assortment of prebiotic molecules did arise in some fashion, and from this assortment those with properties favorable for
the processes that we now associate with life began to interact and to form more complicated compounds. The processes
through which modern organisms synthesize molecular building blocks will be discussed in Chapters 24, 25, and 26.
I. The Molecular Design of Life 2. Biochemical Evolution 2.1. Key Organic Molecules Are Used by Living Systems
Figure 2.1. The Urey-Miller Experiment. An electric discharge (simulating lightning) passed through an atmosphere of
CH
4
, NH
3
, H
2
O, and H
2
leads to the generation of key organic compounds such as amino acids.
I. The Molecular Design of Life 2. Biochemical Evolution 2.1. Key Organic Molecules Are Used by Living Systems
Figure 2.2. Products of Prebiotic Synthesis. Amino acids produced in the Urey-Miller experiment.
I. The Molecular Design of Life 2. Biochemical Evolution 2.1. Key Organic Molecules Are Used by Living Systems
Figure 2.3. Prebiotic Synthesis of a Nucleic Acid Component. Adenine can be generated by the condensation of HCN.
I. The Molecular Design of Life 2. Biochemical Evolution
2.2. Evolution Requires Reproduction, Variation, and Selective Pressure
Once the necessary building blocks were available, how did a living system arise and evolve? Before the appearance of
life, simple molecular systems must have existed that subsequently evolved into the complex chemical systems that are
characteristic of organisms. To address how this evolution occurred, we need to consider the process of evolution. There
are several basic principles common to evolving systems, whether they are simple collections of molecules or competing
populations of organisms. First, the most fundamental property of evolving systems is their ability to replicate or
reproduce. Without this ability of reproduction, each "species" of molecule that might appear is doomed to extinction as
soon as all its individual molecules degrade. For example, individual molecules of biological polymers such as
ribonucleic acid are degraded by hydrolysis reactions and other processes. However, molecules that can replicate will
continue to be represented in the population even if the lifetime of each individual molecule remains short.
A second principle fundamental to evolution is variation. The replicating systems must undergo changes. After all, if a
system always replicates perfectly, the replicated molecule will always be the same as the parent molecule. Evolution
cannot occur. The nature of these variations in living systems are considered in Section 2.2.5.
A third basic principle of evolution is competition. Replicating molecules compete with one another for available
resources such as chemical precursors, and the competition allows the process of evolution by natural selection to occur.
Variation will produce differing populations of molecules. Some variant offspring may, by chance, be better suited for
survival and replication under the prevailing conditions than are their parent molecules. The prevailing conditions exert a
selective pressure that gives an advantage to one of the variants. Those molecules that are best able to survive and to
replicate themselves will increase in relative concentration. Thus, new molecules arise that are better able to replicate
under the conditions of their environment. The same principles hold true for modern organisms. Organisms reproduce,
show variation among individual organisms, and compete for resources; those variants with a selective advantage will
reproduce more successfully. The changes leading to variation still take place at the molecular level, but the selective
advantage is manifest at the organismal level.
2.2.1. The Principles of Evolution Can Be Demonstrated in Vitro
Is there any evidence that evolution can take place at the molecular level? In 1967, Sol Spiegelman showed that
replicating molecules could evolve new forms in an experiment that allowed him to observe molecular evolution in the
test tube. He used as his evolving molecules RNA molecules derived from a bacterial virus called bacteriophage Q β .
The genome of bacteriophage Q β , a single RNA strand of approximately 3300 bases, depends for its replication on the
activity of a protein complex termed Q β replicase. Spiegelman mixed the replicase with a starting population of Q β
RNA molecules. Under conditions in which there are ample amounts of precursors, no time constraints, and no other
selective pressures, the composition of the population does not change from that of the parent molecules on replication.
When selective pressures are applied, however, the composition of the population of molecules can change dramatically.
For example, decreasing the time available for replication from 20 minutes to 5 minutes yielded, incrementally over 75
generations, a population of molecules dominated by a single species comprising only 550 bases. This species is
replicated 15 times as rapidly as the parental Q β RNA (Figure 2.4). Spiegelman applied other selective pressures by, for
example, limiting the concentrations of precursors or adding compounds that inhibit the replication process. In each case,
new species appeared that replicated more effectively under the conditions imposed.
The process of evolution demonstrated in these studies depended on the existence of machinery for the replication of
RNA fragments in the form of the Q β replicase. As noted in Chapter 1, one of the most elegant characteristics of nucleic
acids is that the mechanism for their replication follows naturally from their molecular structure. This observation
suggests that nucleic acids, perhaps RNA, could have become self-replicating. Indeed, the results of studies have
revealed that single-stranded nucleic acids can serve as templates for the synthesis of their complementary strands and
that this synthesis can occur spontaneously that is, without biologically derived replication machinery. However,
investigators have not yet found conditions in which an RNA molecule is fully capable of independent selfreplication